ECTS2013 Poster Presentations Other diseases of bone and mineral metabolism (48 abstracts)
A OPTN variant (rs1561570) interacts with TNFRSF11A polymorphism (rs1805034) on the clinical phenotype of sporadic Paget's disease of bone
Daniela Merlotti 1 , Luigi Gennari 1 , Fernando Gianfrancesco 2 , Domenico Rendina 3 , Marco Di Stefano 4 , Teresa Esposito 2 , Giuseppina Divisato 2 , Giovanna Morello 2 , Riccardo Muscariello 3 , Giancarlo Isaia 4 , Pasquale Strazzullo 3 & Ranuccio Nuti 1
1Department of Medical Surgical Sciences and Neurosciences, University of Siena, Siena, Italy; 2Institute of Genetics and Biophysics, CNR, Naples, Italy; 3Department of Clinical and Experimental Medicine, University of Naples Federico II, Naples, Italy; 4Surgical and Medical Disciplines, Section of Gerontology and Bone Metabolic Diseases, University of Turin, Turin, Italy.
Despite mutations in SQSTM1 gene have been detected in up to 50% of patients with familial Paget’s disease of bone (PDB), their prevalence is low in sporadic PDB, likely due to the presence of additional predisposition genes. Recently, at least seven genes were associated with PDB in genome-wide-association studies, including polymorphic variation in OPTN,encoding for optineurin. In particular, a single OPTN variant (rs1561570) was highly associated with PDB in our Italian replication cohort of 205 SQSTM1-negative patients. In this study we evaluated whether this OPTN variant is associated with PDB and the severity of phenotype in a larger population of 735 cases previously screened for SQSTM1 mutations. 200 age and sex-matched controls were also genotyped for comparison. Potential interactions with a TNFRSF11A polymorphism (rs1805034) previously associated with PDB severity were also explored. In the overall population we observed an increased prevalence of rs1561570 T allele in PDB patients than in controls (OR 1.6; P<0.01). This association was higher in sporadic than familial cases. In contrast to the TNFRSF11A C variant, which was associated with increased disease severity in both SQSTM1 negative or positive patients, the OPTN variant did not appear to interact with SQSTM1. In fact, the presence of the OPTN risk allele (T) was significantly associated with an early onset and an increased number of affected sites only in SQSTM1 negative patients, and particularly in sporadic cases. Haplotype analysis showed a higher prevalence of haplotype CC-TT (containing the homozygous risk alleles for both TNFRSF11A and OPTN,respectively) in sporadic than familial cases or controls (11 vs 7 vs 3% in sporadic, familial PDB and controls, respectively; P<0.01). In summary, this study provides evidence that this OPTN variant affects the susceptibility to develop PDB and interacts with TNFRSF11A polymorphism to cause the severity of the disorder in sporadic cases.
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Bone Abstracts
ISSN 2052-1219 (online)
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